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Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women's Health Initiative Observational Study

Crandall, Carolyn, J., MD, MS1; Hovey, Kathleen, M., MS2; Andrews, Christopher, A., PhD3; Chlebowski, Rowan, T., MD, PhD4; Stefanick, Marcia, L., PhD5; Lane, Dorothy, S., MD, MPH6; Shifren, Jan, MD7; Chen, Chu, PhD8; Kaunitz, Andrew, M., MD9; Cauley, Jane, A., DrPH10; Manson, JoAnn, E., MD, DrPH11

doi: 10.1097/GME.0000000000000956
Original Articles

Objective: To determine the association between use of vaginal estrogen and risk of a global index event (GIE), defined as time to first occurrence of coronary heart disease (CHD), invasive breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, or death from any cause.

Methods: For this prospective observational cohort study, we used data from participants of the Women's Health Initiative Observational Study, who were recruited at 40 US clinical centers, aged 50 to 79 years at baseline and did not use systemic estrogen therapy during follow-up (n = 45,663, median follow-up 7.2 years). We collected data regarding incident CHD, invasive breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, death, and self-reported use of vaginal estrogen (cream, tablet). We used Cox proportional-hazards regression models to adjust for covariates.

Results: Among women with an intact uterus, the risks of stroke, invasive breast cancer, colorectal cancer, endometrial cancer, and pulmonary embolism/deep vein thrombosis were not significantly different between vaginal estrogen users and nonusers, whereas the risks of CHD, fracture, all-cause mortality, and GIE were lower in users than in nonusers (GIE adjusted hazard ratio 0.68, 95% confidence interval 0.55-0.86). Among hysterectomized women, the risks of each of the individual GIE components and of the overall GIE were not significantly different in users versus nonusers of vaginal estrogen (GIE adjusted hazard ratio 0.94, 95% confidence interval 0.70-1.26).

Conclusions: The risks of cardiovascular disease and cancer were not elevated among postmenopausal women using vaginal estrogens, providing reassurance about the safety of treatment.

1Department of Medicine, University of California at Los Angeles, Los Angeles, CA

2Department of Epidemiology and Environmental Health, University at Buffalo, The State University of New York, Buffalo, New York, NY

3Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI

4Department of Medical Oncology and Therapeutics, City of Hope National Medical Center, Duarte, CA

5Departments of Medicine and Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA

6Department of Family, Population and Preventive Medicine, Stony Brook University School of Medicine, Stony Brook, New York, NY

7Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA

8Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, D.C.

9Department of Obstetrics and Gynecology, University of Florida College of Medicine, Jacksonville, FL

10Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA

11Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Address correspondence to: Carolyn J. Crandall, MD, MS, Department of Medicine, University of California at Los Angeles, Los Angeles, CA. E-mail:

Received 18 April, 2017

Revised 23 June, 2017

Accepted 23 June, 2017

Funding: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.

Conflicts of interest: The following authors have no conflicts to disclose: C.J.C., K.M.H., J.E.M., C.C., D.S.L., J.A.C., C.A., M.L.S. A.M.K. serves as a consultant for Allergan, Inc; AMAG, Pfizer Inc; and Shionogi. He receives research grants (funds paid to University of Florida) from TherapeuticsMD. He receives royalties from UpToDate. R.T.C. serves as consultant for Amgen, Genentech, Novartis, Astra-Zeneca, and Pfizer. He also is on speaker's panel for Genentech and Novartis. J.L.S. serves as a research consultant to the New England Research Institutes.

© 2018 by The North American Menopause Society.